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dc.creatorVidenović, Milica
dc.creatorOpsenica, Dejan
dc.creatorBurnett, James C.
dc.creatorGomba, Laura
dc.creatorNuss, Jonathan E.
dc.creatorSelaković, Života
dc.creatorKonstantinović, Jelena M.
dc.creatorKrstic, Maja
dc.creatorŠegan, Sandra
dc.creatorZlatović, Mario
dc.creatorSciotti, Richard J.
dc.creatorBavari, Sina
dc.creatorŠolaja, Bogdan
dc.date.accessioned2019-01-30T17:42:36Z
dc.date.available2019-01-30T17:42:36Z
dc.date.issued2014
dc.identifier.issn0022-2623
dc.identifier.urihttp://cer.ihtm.bg.ac.rs/handle/123456789/1580
dc.description.abstractSignificantly more potent second generation 4-amino-7-chloroquinoline (4,7-ACQ) based inhibitors of the botulinum neurotoxin serotype A (BoNT/A) light chain were synthesized. Introducing an amino group at the C(3) position of the cholate component markedly increased potency (IC50 values for such derivatives ranged from 0.81 to 2.27 mu M). Two additional subclasses were prepared: bis(steroidal)-4,7-ACQ derivatives and bis(4,7-ACQ)cholate derivatives; both classes provided inhibitors with nanomolar-range potencies (e.g., the K-i of compound 67 is 0.10 mu M). During BoNT/A challenge using primary neurons, select derivatives protected SNAP-25 by up to 89%. Docking simulations were performed to rationalize the compounds' in vitro potencies. In addition to specific residue contacts, coordination of the enzyme's catalytic zinc and expulsion of the enzyme's catalytic water were a consistent theme. With respect to antimalarial activity, the compounds provided better IC90 activities against chloroquine resistant (CQR) malaria than CQ, and seven compounds were more active than mefloquine against CQR strain W2.en
dc.publisherAmerican Chemical Society (ACS)
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/172008/RS//
dc.relationNational Cancer Institute, National Institutes of Health (U.S.) [HHSN261200800001E]
dc.relationNational Institute of Allergy and Infectious Diseases (U.S.) [5-U01AI082051-02]
dc.rightsopenAccess
dc.sourceJournal of Medicinal Chemistry
dc.titleSecond Generation Steroidal 4-Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease and P. falciparum Malariaen
dc.typearticle
dc.rights.licenseARR
dcterms.abstractСолаја, Богдан A.; Сциотти, Рицхард Ј.; Бавари, Сина; Бурнетт, Јамес Ц.; Константиновиц, Јелена; Крстиц, Маја; Опсеница, Дејан; Шеган, Сандра; Селаковиц, Зивота; Виденовиц, Милица; Златовиц, Марио; Нусс, Јонатхан Е.; Гомба, Лаура;
dc.citation.volume57
dc.citation.issue10
dc.citation.spage4134
dc.citation.epage4153
dc.citation.other57(10): 4134-4153
dc.citation.rankaM21
dc.identifier.pmid24742203
dc.identifier.doi10.1021/jm500033r
dc.identifier.rcubConv_3152
dc.identifier.fulltexthttp://cer.ihtm.bg.ac.rs//bitstream/id/8046/1578.pdf
dc.identifier.scopus2-s2.0-84901253130
dc.identifier.wos000336510100017
dc.type.versionpublishedVersion


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